Byrd Alzheimer's Institute and.
Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida, USA.
J Clin Invest. 2021 Feb 15;131(4). doi: 10.1172/JCI126299.
Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell's response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer's disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.
tau 病显示出从认知到情感行为障碍的表型谱；然而，促进 tau 病理学的机制以及 tau 如何引起行为障碍仍然不清楚。我们报告了多胺代谢、行为障碍和 tau 命运之间的独特相互作用。多胺是支持神经元功能、轴突完整性和认知处理的普遍存在的脂族分子。多胺代谢的短暂增加标志着细胞对各种损伤的反应，称为多胺应激反应（PSR）。在阿尔茨海默病（AD）大脑中观察到与多胺代谢相关的基因转录物的失调，我们发现鸟氨酸脱羧酶抗酶抑制剂 2（AZIN2）增加的幅度最大。我们表明，持续的 AZIN2 过表达在具有潜在 tau 病（MAPT P301S；PS19）的小鼠中引起了适应性不良的 PSR。AZIN2 还增加了乙酰多胺，增加了 tau 沉积，并促进了认知和情感行为障碍。较高阶的多胺取代微管相关 tau，以促进聚合，但也降低了 tau 成核和寡聚化。相反，乙酰多胺促进了 tau 的成核和寡聚体。这些数据表明，tau 病引发了改变的酶学特征，支持疾病进展的前馈循环。总之，tau 诱导的 PSR 会影响行为和疾病的持续时间，但也可能使多胺途径成为 tau 病包括 AD 的潜在靶点和治疗的潜在切入点。
